Long-term brain fog and cognitive impairment in previously hospitalized COVID-19 patients

Objectives Limited research exists on COVID-19 associated brain fog, and on the long-term cognitive and psychiatric sequelae in racially and ethnically diverse patients. We characterize the neuropsychological sequelae of post-acute COVID-19 in a diverse cohort and investigate whether COVID-19 clinical severity remains associated with brain fog and cognitive deficits approximately 2 years post infection. Methods A cross-sectional study of patients with a history of COVID-19 hospitalization (March-September 2020). COVID-19 clinical severity was indexed using the National Early Warning Score 2 and a comprehensive neuropsychological tele-battery was administered 2 years post discharge. Pearson’s r correlations assessed association, while independent sample t-tests examined group differences. Significant outcomes were further analyzed using multiple regression and ANCOVAs, adjusting for key covariates. Results In 41 adult patients (19 female, 30 Hispanic, 13 Black, mean age of 65 (SD = 15), COVID-19 level of severity was associated with greater number of endorsed brain fog symptoms (Pearson’s r = .34, 95% CI [.04, .59]), worse overall cognitive functioning (global cognition: r = -.36, 95% CI [-.61, -.05]) and reduced performance on an attention and working memory task (digit span backwards: r = -.41, 95% CI [-.66, -.09]) at 2-year follow-up. Brain fog symptoms most associated with COVID-19 severity included difficulty focusing (r = .46, 95% CI [.18, .67]), detached (r = .41, 95% CI [.12, .64]) and feeling sleepy (r = .40, 95% CI [.11, .63]). Patients’ cognitive performance was generally below average (global cognition z-score: M = -.96, SD = .66), with group differences based on sex and ethnicity evidenced on individual cognitive tests. Discussion This study emphasizes the importance of continued research on the long-term effects of COVID-19 infection on neuropsychological outcomes, particularly among underrepresented, health-disparate groups. Greater understanding of these associations could improve detection and treatment of those at increased risk of cognitive decline or impairment.


Background
COVID-19 continues to affect millions of people globally [1].While the initial focus of research and treatment was on the acute respiratory and physiological symptoms caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) , there is growing evidence of the neuropsychological post-acute sequelae of COVID-19 (PASC) [1,2].Over 200 million people worldwide continue to experience long-term COVID-19 related symptoms [3], with about 50% of patients exhibiting at least one symptom 12 months after acute infection [4].Previous studies have documented neuropsychological features of PASC at 4, 6 and 12 months [5][6][7].One recent prospective cohort study in Sweden conducted 165 telephone interviews at 4 months post hospital discharge and again at 24 months [8].Results at 24 months suggested that most patients had decreased quality of life due to ongoing symptoms.Consistent with previous coronavirus outbreaks [9], studies suggest that PASC is associated with persistent neuropsychological and psychiatric issues, especially in individuals hospitalized with severe COVID-19.Additionally, pre-existing comorbidities may become exacerbated in these individuals, quality of life may worsen, and survivors are at increased risk of experiencing worse health outcomes [10].The persistent neuropsychological and psychiatric effects of PASC, including cognitive impairment, depression, anxiety, and sleeplessness are a growing cause for concern [11].Subjective cognitive issues, known as "brain fog", including forgetfulness, difficulty concentrating, and mental fatigue [12], are frequently reported [13].Many post-acute COVID-19 survivors exhibit measurable difficulties with memory, attention, and executive function [5], however levels of impairment and affected domains remain unclear.
Underrepresented groups in the United States, such as Hispanics, Blacks, and women, may be at a higher risk of PASC [14].Although further research is needed to identify the mechanisms behind this increased risk, it is likely influenced by disparities in the biological and social determinants of health [15].Hispanics and Blacks were overwhelmingly affected by acute COVID-19 morbidity and mortality [16].The impact of PASC on these populations is less well known, but preliminary research suggests they have a higher prevalence of cognitive issues and disproportionate rates of mood disorders [10,17].Women are three times more likely to be diagnosed with PASC [18].Considering these demographic groups remain underrepresented in COVID-19 research and clinical research at large [19,20], it is critical to accurately characterize the neuropsychological outcomes of PASC and identify associated risk factors.
The focus of this study was to administer a comprehensive neuropsychological tele-battery to evaluate long-term associations between brain fog, objective assessment of cognitive function, and self-reported psychiatric measures of mood and sleep quality in a racially and ethnically diverse cohort.While our primary aim was to characterize the neuropsychological profile of this cohort, we expected that patients who experienced the highest COVID-19 clinical severity while hospitalized would exhibit worse long-term neuropsychological outcomes.
were fluent in the patient's preferred language of testing (English or Spanish), with an administration time of approximately 35-45 minutes.Patients were instructed to find a quiet and comfortable place in their home, let others in the home know they would be occupied for 45 minutes and not write anything down.Demographic information was also collected (for list see Table 1).
Self-reported brain fog and psychiatric measures.Self-report measures included the Patient Health Questionnaire-9 (PHQ-9) [22], to assess for depression, the Generalized Anxiety Disorder-7 (GAD-7) [23], to assess anxiety, the Pittsburgh Sleep Quality Index (PSQI) [24], to evaluate sleep quality, and a Brain Fog Questionnaire (BFQ) adapted from Ross et al [25], to measure brain fog symptoms.The BFQ consists of 19 items which assess various aspects of brain fog symptoms, such as exhaustion, difficulty with concentration, forgetfulness, mental confusion, and difficulty with word finding.For each item, patients were asked to endorse ("yes" = 1 or "no" = 0) whether they have experienced the given symptom within the past two weeks.Each item on the BFQ was also rated on a Likert scale to gauge both frequency (0 = Never to 7 = All Day) and severity (1 = Mild, 2 = Moderate, 3 = Severe).The total score represents the sum of all 19 endorsed brain fog items and ranges from 0 to 19, with higher scores indicating greater severity.For a description of the self-report psychiatric measures administered to participants, such as the PHQ-9, GAD-7 and PSQI, see the S1 File.Standardized cognitive assessments.The comprehensive battery included validated standardized measures of verbal learning and memory, such as the Hopkins Verbal Learning Test-Revised [26,27], the Controlled Oral Word Association Test letters (FAS letters for English and PTM letters for Spanish speakers) and verbal and category fluency, tests (animals and fruits) [28][29][30][31], processing speed and executive set-shifting, were assessed with the Oral Trail Making Test parts A and B (OTMT) [32], and attention and working memory with the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span subtests (forward, backward, sequence) [33,34].Normative samples were derived to calculate standardized Z-scores for cognitive measures among both English and Spanish speaking patients.The validity of inhome tele-based administration of these measures has been documented elsewhere [35][36][37].
Variables linked to COVID-19 from admission through hospitalization.Variables included number of days in the hospital, pre-morbid medical diagnoses and diagnoses at discharge, level of respiratory distress including acute respiratory distress syndrome (ARDS), acute hypoxic respiratory failure (AHRF) and shortness of breath (SOB), and type of respiratory support while in the hospital.For calculating COVID-19 clinical severity via the National Early Warning Score 2 (NEWS2) [38], vitals associated with lowest SpO2 (saturation of peripheral oxygen) and hypercapnic status were captured and variables input included respiratory rate, status of hypercapnic respiratory failure (yes/no), room air or supplemental oxygen (yes/no), temperature, systolic blood pressure, pulse, status of consciousness ('alert' or 'newonset confusion (or disorientation/agitation), responds to voice, responds to pain or unresponsive').NEWS2 scores are categorized into low (0-4), medium (5-6), and high (�7) clinical risk.

Statistical analysis
For our primary outcome, the characterization of brain fog was made via review of descriptive statistics of individual questionnaire symptom items with a specific focus on item prevalence.Pearson's r correlation analyses were conducted to assess the association between BFQ item frequencies with measures of COVID-19 clinical severity (NEWS2), depression (PHQ-9), anxiety (GAD-7) and sleep disturbance (PSQI).Pearson's r correlations were run to assess the association between BFQ total scores with COVID-19 clinical severity, depression, anxiety, sleep disturbance, and cognition as well as demographic variables of age and total comorbidities.Group differences in BFQ total score based on sex, ethnicity, and level of respiratory distress were assessed with independent sample t-tests.
For our secondary outcome of cognition, scores were standardized (z-scores) based on previously documented normative samples.An index of global cognitive functioning was calculated as the average of standardized z-scores across all cognitive measures.The characterization of cognitive and psychiatric measures was made via review of descriptive statistics and independent sample t-tests to assess differences based on sex and ethnicity.
For our final outcome Pearson's r correlation analyses were run to assess the association between COVID-19 clinical severity (NEWS2) and cognitive and psychiatric outcomes.Independent sample t-tests were also run to evaluate group differences based on inpatient diagnosis of acute respiratory distress syndrome (ARDS) or acute hypoxemic respiratory failure (AHRF) versus those with either shortness of breath (SOB) or no respiratory symptoms on physical exam.
Standard multiple regression and analyses of covariance (ANCOVAs) were run to determine whether corresponding significant findings from Pearson's r correlations and t-tests remained after controlling for relevant covariates (i.e., demographic variables and total number of medical comorbidities, etc.)

Results
The characteristics of the study sample are shown in Table 1.Among all 41 patients (46% female; age M = 65.1,SD = 15.1), 25 (61%) were tested in Spanish.Duration of hospitalization ranged from 2 to 96 days (M = 15, SD = 19) and time from discharge to date of testing ranged between 17 to 26 months (M = 22.2, SD = 2.1).Based on the NEWS2 categories, 14.6% of the sample experienced mild, 43.9% experienced medium, and 41.5% had a history of high COVID-19 clinical severity.
Due to interruption in testing procedures, one patient did not complete the PHQ-9, GAD-7 and PSQI and 2 patients did not complete any of the cognitive tests.Two additional participants did not complete the OTMT, and 4 patients' WAIS-IV Digit Span data were removed due to evidence of cheating.A complete-case analysis approach was utilized.As such, participants with missing data were not included in relevant tests.

Characterization of brain fog and associated variables
On average, patients endorsed approximately seven of the possible 19 BFQ items (BFQ Total M = 7.1, SD = 5.3) and 87.8% of the sample endorsed at least one item.The prevalence of each BFQ item ranged from 65.9% to 14.6% (see Table 2) with a gradual linear (vs.stepwise) decline in prevalence when ordered from highest to lowest (see Fig 1).The top 5 BFQ items included exhausted, forgetful, sleepy, slow, and easily distracted.Pearson's r correlations revealed the items most strongly associated with COVID-19 clinical severity (NEWS2) included difficulty focusing, detached, sleepy, spacey, slow, difficulty processing what others say, and annoying.Most BFQ items were associated with depression (PHQ-9) and sleep disturbance (PSQI), while relatively fewer were significantly associated with anxiety (GAD-7) (see Table 2).
Brain fog total scores were significantly associated with depression, anxiety, sleep disturbance, and COVID-19 clinical severity (see Table 3).Brain fog was not associated with age or number of comorbidities.The only cognitive measure associated with BFQ total score was WAIS-IV digit span backward; however, this effect was non-significant after controlling for depression (partial correlation r = -.12,p = .49).

Cognitive assessments, psychiatric measures, and associated variables
On average, patients in the sample performed approximately 1 standard deviation below the mean, as determined by respective normative samples (see Table 4).The greatest deficits were evidenced on tasks of verbal memory recognition (HVLT-R Recognition), letter fluency (COWAT FAS/PTM), and processing speed (OTMT Part A).Patients' performance was relatively better on measures of attention and working memory (WAIS-IV digit span total), particularly on digit span backward.See Fig 2 for graphic illustration of standardized (Z-score) averages for all cognitive tests.Demographic group differences indicated that females were slower than males on OTMT Part A. These differences remained significant per follow-up analyses of covariance (ANCOVA), testing group differences in sex while controlling for ethnicity, time since discharge and total comorbidities (F (1, 32) = 6.51, p = .02,partial eta-squared (η p 2 ) = .17).Group differences based on ethnicity were also evidenced indicated that Hispanics performed worse than non-Hispanics on tests of letter fluency (COWAT FAS/PTM) and speeded executive set-  shifting (OTMT Trails B)..These effects also remained significant in follow-up ANCOVA analyses controlling for sex, time since discharge and total comorbidities (FAS/PTM: F(1, 34) = 4.64, p = .04,η p 2 = .12;OTMT Trails B: F(1, 32) = 11.66,p = .002,η p 2 = .27).
On average, reports of both depression and anxiety fell within the mild range (see Table 3).Thirty-five percent of the sample reported symptoms consistent with a moderate level of depression or higher, while 18% of the patients did so for anxiety.On the PSQI, 75% of the sample reported symptoms indicating elevated sleep disturbance.
Sleep disturbance was positively associated with total number of comorbidities, but not with age, sex, or ethnicity.Depression and anxiety were not found to significantly correlate with these measures (see Table 3).

A.
Pearson Similarly, independent sample t-tests looking at differences based on diagnosed respiratory distress (i.e., ARDS/AHRF vs. SOB/None) revealed that those diagnosed with respiratory distress performed worse on WAIS-IV digit span backward and OTMT Part B. These group differences were also marginally significant for global cognition, indicating that those with a history of ARDS/AHRF (M = -1.13,SD = 0.56) were somewhat worse than those with history of SOB/None (M = -0.71,SD = 0.74), (t( 37 for bar graphs demonstrating these group differences.No significant associations or group differences were found between all psychiatric measures and either NEWS2 or respiratory distress groups, respectively (see Table 3).

Discussion
In this study, we describe brain fog, cognitive, and psychiatric sequalae, in a racially and ethnically diverse cohort of adults with a history of hospitalization due to COVID-19.Our findings highlight how prevalent brain fog symptoms such as exhaustion, forgetfulness and slowed processing are in previously hospitalized PASC patients, and how brain fog is associated with depression, sleep disturbances and anxiety.Cognitive deficits were also apparent, especially in areas of verbal memory, letter fluency and processing speed.COVID-19 clinical severity was linked to worse cognitive outcomes, particularly in global cognition and working memory.
Walgren et al's population based longitudinal study in Sweden found that 84% of patients reported persistent symptoms at 24 months, with the most common being mental fatigue (65%), difficulty remembering (60%), weakness (58%) and word finding difficulties (40%) [6].The results showed that most patients experienced persistent sequalae and impaired quality of life, with fatigue being the most cited.They also found that women and individuals with preexisting conditions were more likely to have ongoing problems.Our results also demonstrated a high prevalence of symptoms, with patients endorsing 7 on average.Those who had greater COVID-19 clinical severity (as indexed by the NEWS2) endorsed more brain fog symptoms overall.Our findings showed that brain fog complaints may not reflect objective cognitive findings.This emphasizes the value of objective testing of perceived deficits.Our results also reinforce Walgren et al's conclusions that some post-acute COVID-19 survivors experience persistent subjective cognitive and affective symptoms two years after infection [8].We also found that brain fog total score was significantly associated with depression, anxiety, and sleep disturbance.In their original BFQ paper, Ross et al reported that sleep disturbances (particularly the presence of comorbid sleep disorders) may affect brain fog as well as negatively impacting cognitive performance [25].Thereby, it is also likely that similar to findings by Graham et al [39], a subset of patients reporting subjective complaints may be affected by other psychiatric features factoring into their brain fog symptoms.These findings highlight the need for continued monitoring and support for patients with post-COVID-19 condition, particularly those with pre-existing conditions and women.
We also investigated cognitive performance and psychiatric symptoms and whether these variables correspond with demographic and self-report measures.For the cognitive assessments, we standardized the scores using normative reference groups.On average, patients exhibited poor cognitive performance compared to the normative samples.Consistent with brain fog reports of word finding difficulties and feeling forgetful, test scores on the Controlled Oral Word Association Test (COWAT) letters and the HVLT-R recognition were notably deficient, implying difficulties with phonemic fluency and memory.In line with brain fog complaints of slowness and suggestive of poor processing speed, scores for the Oral Trails A were also deficient.Demographic differences were observed, with females scoring poorly on processing speed compared to males and Hispanics exhibiting poorer performance on phonemic fluency, semantic fluency and executive set shifting than non-Hispanics.The extent to which previous acute COVID-19 infection contributes to these differences is unknown, however it is possible that other underlying factors might be involved such as cultural or language differences.Hispanics also experience a high prevalence of comorbidities such as type 2 diabetes, which has been linked to an increased risk of cognitive decline [40].Additionally, psychosocial, and socioeconomic factors such as lower educational attainment and lower income may be contributing factors [41].
We also examined the influence of COVID-19 clinical severity on cognitive and psychiatric outcomes.COVID-19 clinical severity was significantly associated with poorer performance on digit span backward and global cognition.Individuals who experienced acute hypoxic respiratory failure (AHRF) or acute respiratory distress syndrome (ARDS) while hospitalized performed significantly worse on working memory and executive set shifting tasks and had marginally worse global cognition.These findings corroborate earlier research reporting executive dysfunction in PASC patients [42].It is important to consider that 35% of our sample met criteria for moderate to severe depression, thus we cannot disentangle these findings from previous research reporting executive dysfunction due to depression [43].There may be other etiological factors contributing to the neuropsychological symptoms of PASC.One prominent hypothesis is that infection induced neuroinflammation and hypoxic-ischemic tissue damage may play a role in the presentation of these features [44].
This study has multiple limitations, including a small sample size and the lack of control group.While we were able to assess the cognitive and psychiatric symptoms, we do not know if what was captured is indeed due to prior COVID-19 infection or other factors (i.e., post intensive care syndrome, social isolation, socioeconomic stressors, etc.)While the initial pool of potential participants was 282, 41 patients could be reached and agreed to participate, introducing a possible selection bias.Ross et al acknowledge that their BFQ demonstrated validity in a postural orthostatic tachycardia syndrome sample [25].However, our study is the first known use of the BFQ in COVID-19 patients, thus further research is needed to assess its validity in this new population.We back translated the BFQ for use with Spanish speaking patients, which is a novelty of this study considering the lack of research in this demographic.It is worth noting that the validity of the BFQ in Spanish has yet to be established.In terms of battery administration, employing face to face testing or HIPAA compliant visual telehealth methods, rather than phone, would provide better controlled testing conditions.While there were issues with completing the battery over the telephone, it is a strength in that we were able to reach patients who may not come to a research site for assessment due to health-related disabilities, mobility, or transportation issues.

Conclusion
The study provides data on the post-acute long-term cognitive and psychiatric sequalae in underrepresented ethnic and racial groups.It underscores the prevalence of brain fog in post COVID-19 patients and its relationship to cognition, depression, anxiety, sleep, demographics, and COVID-19 severity.